The pharma industry is looking to novel technologies for answers to its challenges in all areas of drug development. Such technologies must be able to adhere to GMP for both clinical and commercial manufacturing.  An essential step prior to commencing clinical trials is the correct implementation of GMP practices to protect patients from quality and safety issues. That’s why it is vital to incorporate GMP expertise alongside novel technologies that can enhance the properties of active pharmaceutical ingredients (APIs) and dosage forms.

One such technology is nanoparticle engineering, which can address the growing challenge of poor aqueous solubility in new drug candidates. Oral drugs with poor aqueous solubility are not well absorbed in the gastrointestinal tract. This leads to poor bioavailability and, in many cases, failure to achieve adequate concentrations in the blood for the desired therapeutic effect to occur.

By reducing the size of drug particles as part of a controlled process, nanoparticle engineering can increase the active surface area and thus the dissolution rate and, if small enough (<50nm), the intrinsic solubility of APIs. By improving absorption and lowering the required dose, novel particle size reduction technologies may even be able to reduce adverse effects to tackle the problem of poor medication adherence.

However, before these benefits can be realized to improve the lives of patients, GMP approval is a key milestone that must be reached. Possessing GMP manufacturing capabilities in-house is critical to providing continuity for partners who wish to progress to the next stage, helping increase the uptake of nanoparticle-based innovations.

A powerhouse for the future: CESS^® nanoparticle engineering
An example of a game-changing nanoparticle engineering technology is Nanoform’s Controlled Expansion of Supercritical Solutions (CESS^®) process. CESS^® works by dissolving powdered API in supercritical carbon dioxide and recrystallizing under controlled temperature and pressure to create uniform API nanoparticles. As CESS^® leverages only supercritical carbon dioxide as its solvent, which can be recycled, it is a green process. Moreover, using CESS^® it is possible to fine-tune particle size and morphology. The award-winning technique is the only process on the market capable of producing nanoparticles as small as 10nm in some cases, and opens up an array of exciting opportunities.

For instance, reducing particle size to this extent could allow drugs to cross biological membranes that were previously impassable, such as the alveoli in the lungs, epithelial barriers in the eye and even potentially the blood-brain barrier. Novel nanoparticle-based treatments administered locally at the site of disease can, by bypassing systemic delivery, result in fewer side effects. Additionally, the ability to reach difficult areas can facilitate more targeted therapeutic interventions for diseases such as pulmonary fibrosis or currently incurable central nervous system disorders. As a consequence of the remarkable capabilities of CESS^®, its use could potentially double the number of drugs that reach the market.

Laying the analytical groundwork
The potential for innovative technologies such as CESS^® to dramatically change the pharmaceutical landscape is clear. However, an enormous amount of work must take place behind the scenes to make that dream a reality with GMP-manufactured nanoformed drugs. Firstly, for each drug candidate, thorough characterization of the API is essential to minimize disruption later down the line during GMP manufacturing.

For poorly soluble nanoparticle drugs, the process of measuring critical quality attributes and defining process parameters and performance attributes is similar to any other drug substance. These provide essential touchpoints to ensure the drug substance remains within safe and efficacious limits.  However, it is especially important to monitor any changes in crystallinity or particle size as even small alterations can drastically impact bioavailability, and thus efficacy. At this stage, transmission electron microscopy (TEM) and scanning electron microscopy (SEM) can be helpful, with sufficient resolution at the nanoscale. Additionally, it is essential to monitor impurities and either prevent them from forming or ensure they remain at safe levels.

Following work to define the critical quality attributes, when standardizing the manufacturing process, techniques such as dynamic light scattering or laser diffraction can be helpful to monitor the drug substance from a quality control (QC) perspective. Meanwhile, techniques such as differential scanning calorimetry (DSC) can be employed to monitor the amorphous state of the drug substance and ensure it remains within strict limits.

While defining limits is a crucial step, flexibility is also vital when working with partners to take their drug from R&D to GMP manufacturing, which goes hand in hand with an expert team that is able to adapt processes to suit clients’ needs. For example, during the development stage, Nanoform may employ a bespoke AI tool to determine particle size distributions from SEM images. However, during a tech transfer process this can be transferred to more conventional dynamic light scattering methods to ease the transition. Whatever the processes ultimately deemed most suitable for a specific drug, good characterization of solid-state material properties is invaluable.

Partnering with a GMP expert
In addition to carrying out rigorous analytical work, partnering with a novel technology company that has the resources to manufacture to GMP standards in-house can also help to make the transition more seamless.

Nanoform has built an expert team that can take APIs from proof-of-concept to proof-of-process all the way through to GMP manufacturing. By leveraging an in-depth knowledge of the API gained over the course of analytical work, the journey to GMP manufacturing can be streamlined. To aid in this, Nanoform has a “pilot line” at the R&D stage with a similar process to GMP manufacturing, which can make the transfer smoother. Additionally, as CESS^® is suitable for continuous manufacturing the process of producing nanoparticles is inherently scalable in itself.

Reaching new horizons through GMP expansion
In today’s pharmaceutical development pipeline, about 70% to 90% of the molecules under development are poorly soluble and could benefit from nanoparticle engineering. In recognition of this, Nanoform has embarked on an ambitious GMP expansion project to help meet the demand for CESS^®-nanoformed drugs manufactured to GMP standards for use in clinical trials. 

In 2022, Nanoform will triple its nanoforming GMP API manufacturing capacity, adding two new CESS^® manufacturing suites in class-D cleanrooms. Nanoform has also invested in state-of-the-art GMP analytical capabilities and a new QC GMP lab on site. The two additional manufacturing suites, together with the GMP analytical characterization laboratories, are geared to handle highly potent compounds (OEL <30 ng/m³).

The expansion is expected to be operational in the fourth quarter of 2022, moving at an unprecedented rate. Future plans to have GMP manufacturing capacity in both the USA and Europe will help to ensure security of supply for essential medicines.

However, a state-of-the-art GMP manufacturing facility is nothing without a skilled team to run it. In order to help assure success, Nanoform carefully assembled a GMP team incorporating expertise from across the value stream, from QC and QA to engineering, and production and technical teams. Furthermore, to ensure that any issues that arise can be addressed rapidly, the production and engineering, QA and QC teams will be available on shift even during late hours.

GMP to meet tomorrow’s challenges
In order to maximize the uptake of game-changing technological innovations, novel technology companies must embrace GMP manufacturing and provide continuity to their partners. By increasing its GMP capacity, Nanoform can take on more projects and increase customers’ drug development success, ultimately allowing more patients to benefit from life-changing medicines.

Get in touch to find out more about Nanoform’s GMP manufacturing capabilities, commercial@nanoform.com